DOCSLIB.ORG

Two Forms of Astrocyte Calcium Excitability Have Distinct Effects on NMDA Receptor-Mediated Slow Inward Currents in Pyramidal Neurons

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Two Forms of Astrocyte Calcium Excitability Have Distinct Effects on NMDA Receptor-Mediated Slow Inward Currents in Pyramidal Neurons The Journal of Neuroscience, June 25, 2008 • 28(26):6659–6663 • 6659 Brief Communications Two Forms of Astrocyte Calcium Excitability Have Distinct Effects on NMDA Receptor-Mediated Slow Inward Currents in Pyramidal Neurons Eiji Shigetomi,1,2 David N. Bowser,3 Michael V. Sofroniew,2 and Baljit S. Khakh1,2,3 Departments of 1Physiology and 2Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, California 90095-1751, and 3Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom 2ϩ Astrocytes display excitability in the form of intracellular calcium concentration ([Ca ]i ) increases, but the signaling impact of these for 2ϩ neurons remains debated and controversial. A key unresolved issue is whether astrocyte [Ca ]i elevations impact neurons or not. Here we report that in the CA1 region of the hippocampus, agonists of native P2Y1 and PAR-1 receptors, which are preferentially expressed in 2ϩ astrocytes, equally elevated [Ca ]i levels without affecting the passive membrane properties of pyramidal neurons. However, under conditions chosen to isolate NMDA receptor responses, we found that activation of PAR-1 receptors led to the appearance of NMDA receptor-mediated slow inward currents (SICs) in pyramidal neurons. In stark contrast, activation of P2Y1 receptors was ineffective in 2ϩ this regard. The PAR-1 receptor-mediated increased SICs were abolished by several strategies that selectively impaired astrocyte [Ca ]i 2ϩ excitability and function. Our studies therefore indicate that evoked astrocyte [Ca ]i transients are not a binary signal for interactions with neurons, and that astrocytes result in neuronal NMDA receptor-mediated SICs only when appropriately excited. The data thus provide a basis to rationalize recent contradictory data on astrocyte–neuron interactions. Key words: astrocyte; calcium; SIC; gliotransmitter; astrocytic glutamate release; glia Introduction cellular Ca 2ϩ release (Newman, 2003a; Parri and Crunelli, 2003). 2ϩ Astrocytes, a type of glial cell, are found in the brain, and their Moreover, it is now well established that astrocyte [Ca ]i in- close spatial relationship to neurons is well documented (Araque creases trigger release of transmitters into the extracellular space. et al., 2001; Haydon, 2001). In addition to their important house- The evidence in favor of this is derived from a variety of ap- keeping roles (Kofuji and Newman, 2004), increasing evidence proaches, including biochemical, amperometric, and capacitance now suggests that astrocytes also actively participate in neuronal methods, as well as single-vesicle imaging (Araque et al., 2000; function (Haydon, 2001; Newman, 2003b; Fields, 2004; Fields Krzan et al., 2003; Bezzi et al., 2004; Evanko et al., 2004; Kreft et and Burnstock, 2006). al., 2004; Zhang et al., 2004a,b; Bowser and Khakh, 2007a; Jaiswal Astrocytes do not fire action potentials. However, they display et al., 2007). One of the transmitters known to be released from ϩ spontaneous and pharmacologically evoked intracellular Ca 2 astrocytes is glutamate. 2ϩ 2ϩ concentration ([Ca ]i) increases, which represent a form of as- The realization that astrocytes display [Ca ]i elevations and trocyte excitability. Since their initial discovery (Cornell-Bell et that they display calcium-triggered glutamate release raises the 2ϩ al., 1990) in astrocyte cultures, [Ca ]i increases have been ex- possibility that astrocytic glutamate could affect neurons. This tensively studied for in vitro preparations of brain slices (Haydon, issue has been addressed in the past, and we restrict ourselves here 2001; Parri et al., 2001; Newman, 2003b; Fields, 2004), and have to the most pertinent experiments for the CA1 region of the also been recorded from astrocytes in vivo with two-photon cal- hippocampus. In one study, NMDA receptor-mediated slow in- 2ϩ cium imaging from the cortex (Hirase et al., 2004). Thus [Ca ]i ward currents (SICs) were recorded from CA1 pyramidal neu- elevations appear to be a widespread and prevalent feature of rons when (S)-3,5-dihydroxyphenylglycine (DHPG) was used to astrocytes, can be triggered by neuronal activity, and are known activate metabotropic glutamate receptors on astrocytes and thus to occur independently of neuronal activity resulting from intra- 2ϩ trigger [Ca ]i elevations (Fellin et al., 2004). However, a recent study has questioned the use of DHPG because of its attendant Received April 20, 2008; revised May 15, 2008; accepted May 16, 2008. actions on neurons (Fiacco et al., 2007). Instead these authors This work was supported partly by the Medical Research Council, the Whitehall Foundation, and the Stein/ Oppenheimer Endowment Award (B.S.K.) and an Uehara Memorial Foundation Fellowship (Japan) (E.S.). used the creative approach of using an exogenous MrgA1 recep- 2ϩ Correspondence should be addressed to Baljit S. Khakh, Department of Physiology, University of California, Los tor selectively expressed in astrocytes to elevate [Ca ]i within Angeles, 10833 LeConte Avenue, 53-263 CHS, Los Angeles, CA 90095-1751. E-mail: [email protected]. 2ϩ them. They found that when astrocyte[Ca ]i levels were ele- D. N. Bowser’s present address: Howard Florey Institute, University of Melbourne, Parkville, Victoria 3010, vated by activating MrgA1 receptors, this did not result in the Australia. DOI:10.1523/JNEUROSCI.1717-08.2008 appearance of SICs in pyramidal neurons (Fiacco et al., 2007). Copyright © 2008 Society for Neuroscience 0270-6474/08/286659-05$15.00/0 Thus, the starkly contrasting conclusions between groups (Fellin 6660 • J. Neurosci., June 25, 2008 • 28(26):6659–6663 Shigetomi et al. • Astrocyte–Neuron Interactions et al., 2004; Fiacco et al., 2007) leaves open the question of 2ϩ whether astrocyte [Ca ]i elevations impact neurons or not (Tritsch and Bergles, 2007). In the present study, we returned to 2ϩ the issue of whether astrocyte [Ca ]i elevations can cause the appearance of SICs on pyramidal neurons. Materials and Methods Preparation of brain slices and electrophysiological recording. The methods used have been described previously (Khakh et al., 2003; Bowser and Khakh, 2004). Briefly, young [postnatal day 11 (P11)–P19] C57 mice were killed in accordance with institutional procedures. In some cases, GFAP-green fluorescent protein (GFP) mice were used, and these were available from previous work (Garcia et al., 2004). Coronal slices of hip- pocampus (200 or 300 ␮m) were cut (model 1000 or 3000 Plus Vi- bratome) and submerged at room temperature in artificial CSF (aCSF) comprising the following (in mM): 126 NaCl, 2.5 KCl, 1.3 MgCl2,10 D-glucose, 2.4 CaCl2, 1.24 NaH2PO4, and 26 NaHCO3 saturated with 95% O2 and 5% CO2. Experiments were performed with potassium glu- conate or chloride-based internal solution, comprising the following (in Ϫ mM): 120 K gluconate (or Cl ), 10 KCl, 1 MgCl2, 0.03 CaCl2, 0.1 EGTA, 1 ATP, 0.2 GTP, 10 HEPES, and 4 glucose, pH 7.25. The resistance of the pipettes was ϳ4–9M⍀. Cells were visualized with infrared optics (Luigs and Neumann) on an upright microscope (Olympus BX50). We used bath application of agonists. Inward currents were recorded at Ϫ60 mV using pCLAMP 9 software, Multiclamp 900A amplifier, and Digidata 1322A (Molecular Devices). Spontaneous EPSCs were recorded in the presence of bicuculline (10 ␮M) and D-(Ϫ)-2-amino-5-phosphono- pentanoic acid (D-AP5; 10 ␮M). Slow inward currents (Fellin et al., 2004) mediated by extrasynaptic NMDA receptors were recorded in low-Mg 2ϩ buffers (0.13 mM) in the presence of bicuculline (10 ␮M), TTX (1 ␮M), and 6-cyano-2,3-dihydroxy-7-nitroquinoxaline (CNQX; 10 ␮M). Astro- cytes were patched with 4–9 M⍀ electrodes filled with an intracellular solution comprising 123 CsCl, 1 MgSO , 10 HEPES, 1 ATP, 0.2 GTP, pH 4 2ϩ 7.35, and 100 ␮M Alexa Fluor 488 (referred to as Alexa 488 in the text), Figure1. Astrocyte[Ca ]i transientsevokedbyactivationofP2Y1 andPAR-1receptors.A, M Representative images of the stratum radiatum region of the hippocampus with astrocytes and BAPTA (10 m ) as indicated in the text (Jourdain et al., 2007). ϩ 2ϩ 2 ␮ Confocal imaging of astrocyte Ca activity and dialysis. Brain slices showingincreasesin[Ca ]i duringactivationofPAR-1receptorswithTFLLRpeptide(30 M). were loaded at room temperature in the dark with 5 ␮M Fluo-4 AM Arrowheads point to astrocytes showing intracellular calcium transients. B, Exemplar traces 2ϩ (Invitrogen) in aCSF for 60 min, then transferred to dye-free aCSF for at PAR-1- and P2Y1-evoked [Ca ]i transients. C, D, Pooled data for experiments such as those in least 30 min before experimentation to allow for cleavage of the AM ester A.Thegraylinesareindividualcells,andthesolidlinesaretheaveragesfromallcells.Activation 2ϩ group (Porter and McCarthy, 1996). Live astrocytes were predominantly of both P2Y1 and PAR-1 receptors evoked increases in astrocyte [Ca ]i levels. E, The average 2ϩ loaded with the fluorescent dye with these conditions. This was con- normalized traces for [Ca ]i transients evoked by P2Y1 and PAR-1 receptor activation; note firmed by simultaneous acquisition of infrared-differential interference that there was a latency for the PAR-1-mediated responses in relation to those mediated by contrast (IR-DIC) images of astrocytes in the same area. Cells and slices P2Y1 receptors, and their duration was longer. were imaged using an Olympus Fluoview 300 laser-scanning confocal microscope with a 300 mW argon laser, at Ͻ10% power. Emitted green fluorescence was collected through a 515 long-pass filter. Fluoview soft- vesicle exocytosis in culture (Bowser and Khakh, 2007a). PAR-1 ware was used for image acquisition. For BAPTA and Alexa 488 dialysis, receptors are known to be preferentially expressed within astro- the astrocytes were held at Ϫ80 mV, and depolarized to 0 mV for 100 ms cytes of the hippocampus (Weinstein et al., 1995; Junge et al., every 30 s to monitor access resistance. The optimal dialysis time was 2004; Lee et al., 2007). Thus, P2Y1 and PAR-1 receptors are useful empirically determined to be 15 min after patching.
Load more

Recommended publications
  • Deciphering the Physiology Underlying the Rapid Clinical Effects of Perispinal Etanercept in Alzheimer's Disease
    Current Alzheimer Research, 2012, 9, 99-109 99 Deciphering the Physiology Underlying the Rapid Clinical Effects of Perispinal Etanercept in Alzheimer’s Disease Edward Tobinick* 100 UCLA Medical Plaza, Suites 205-210, Los Angeles, California 90095, USA Abstract: Excess tumor necrosis factor (TNF) plays a pivotal role in the pathogenesis of Alzheimer’s disease(AD). Clini- cal improvement following perispinal administration of etanercept in patients with Alzheimer’s disease and other forms of dementia and brain dysfunction is characteristically evident within minutes. The rapidity and constellation of the clinical effects across multiple domains (cognition, mood, memory, motor function, and attention) suggest they are mediated by non-synaptic signaling mechanisms previously unrecognized for etanercept. These mechanisms likely extend beyond the known roles of TNF as a gliotransmitter that modulates synaptic strength, synaptic scaling, and AMPA receptor traffick- ing. Preliminary basic science and clinical investigation suggests that perispinal administration of etanercept may lead to its rapid penetration into the cerebrospinal fluid (CSF) within the cerebral ventricles. Diffusion of large molecules into the periventricular brain parenchyma is known to occur, but this process may not be sufficient to explain the rapidity of the clinical effects. There exist populations of cells, including CSF-contacting neurons and modified ependymal cells called tanycytes, that have receptive surfaces in direct contact with the CSF. It is hypothesized that the rapid clinical effects of perispinal etanercept involve non-synaptic signal transduction across the ependymal barrier and into neuronal networks via these CSF-contacting cells. This hypothesis challenges the dogma that penetration of a therapeutic into the cerebral pa- renchyma through the endothelium of the cerebral vasculature (the so-called blood- brain barrier) is necessary to produce rapid clinical effects in AD.
    [Show full text]
  • Dietary Fat Exacerbates Postprandial Hypothalamic Inflammation Involving Glial Fibrillary Acidic Protein-Positive Cells and Micr
    Dietary fat exacerbates postprandial hypothalamic inflammation involving glial fibrillary acidic protein-positive cells and microglia in male mice Céline Cansell, Katharina Stobbe, Clara Sanchez, Ophélia Le Thuc, Coralie-Anne Mosser, Selma Ben-Fradj, Joris Leredde, Cynthia Lebeaupin, Delphine Debayle, Lucile Fleuriot, et al. To cite this version: Céline Cansell, Katharina Stobbe, Clara Sanchez, Ophélia Le Thuc, Coralie-Anne Mosser, et al.. Di- etary fat exacerbates postprandial hypothalamic inflammation involving glial fibrillary acidic protein- positive cells and microglia in male mice. Glia, Wiley, 2021, 69 (1), pp.42-60. 10.1002/glia.23882. hal-02899910 HAL Id: hal-02899910 https://hal.archives-ouvertes.fr/hal-02899910 Submitted on 5 Nov 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Distributed under a Creative Commons Attribution| 4.0 International License Received: 5 December 2019 Revised: 10 June 2020 Accepted: 11 June 2020 DOI: 10.1002/glia.23882 RESEARCH ARTICLE Dietary fat exacerbates postprandial hypothalamic inflammation involving
    [Show full text]
  • Neuronal Activity Determines Distinct Gliotransmitter Release from a Single Astrocyte Ana Covelo, Alfonso Araque*
    RESEARCH ARTICLE Neuronal activity determines distinct gliotransmitter release from a single astrocyte Ana Covelo, Alfonso Araque* Department of Neuroscience, University of Minnesota, Minneapolis, United States Abstract Accumulating evidence indicates that astrocytes are actively involved in brain function by regulating synaptic activity and plasticity. Different gliotransmitters, such as glutamate, ATP, GABA or D-serine, released form astrocytes have been shown to induce different forms of synaptic regulation. However, whether a single astrocyte may release different gliotransmitters is unknown. Here we show that mouse hippocampal astrocytes activated by endogenous (neuron-released endocannabinoids or GABA) or exogenous (single astrocyte Ca2+ uncaging) stimuli modulate putative single CA3-CA1 hippocampal synapses. The astrocyte-mediated synaptic modulation was biphasic and consisted of an initial glutamate-mediated potentiation followed by a purinergic- mediated depression of neurotransmitter release. The temporal dynamic properties of this biphasic synaptic regulation depended on the firing frequency and duration of the neuronal activity that stimulated astrocytes. Present results indicate that single astrocytes can decode neuronal activity and, in response, release distinct gliotransmitters to differentially regulate neurotransmission at putative single synapses. DOI: https://doi.org/10.7554/eLife.32237.001 Introduction Astrocytes play key roles in brain homeostasis, such as, neurotransmitter uptake, water and ion bal- *For correspondence: ance, and blood flow control (Simard and Nedergaard, 2004; Huang et al., 2004). In addition, [email protected] astrocytes are emerging as cells with relevant roles in synaptic function, being active players of the Competing interests: The Tripartite Synapse (Araque et al., 1999). They express a wide variety of functional receptors that authors declare that no can be activated by neurotransmitters (Araque et al., 2001; Haydon and Carmignoto, 2006; competing interests exist.
    [Show full text]
  • GABA As a Rising Gliotransmitter
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Frontiers - Publisher Connector REVIEW ARTICLE published: 17 December 2014 NEURAL CIRCUITS doi: 10.3389/fncir.2014.00141 GABA as a rising gliotransmitter Bo-Eun Yoon 1 and C. Justin Lee 2,3* 1 Department of Nanobiomedical Science, Dankook University, Chungnam, South Korea 2 WCI Center for Functional Connectomics, Korea Institute of Science and Technology (KIST), Seoul, South Korea 3 Center for Neural Science and Center for Functional Connectomics, Korea Institute of Science and Technology (KIST), Seoul, South Korea Edited by: Gamma-amino butyric acid (GABA) is the major inhibitory neurotransmitter that is known to Alexey Semyanov, University of be synthesized and released from GABAergic neurons in the brain. However, recent studies Nizhny Novgorod, Russia have shown that not only neurons but also astrocytes contain a considerable amount of Reviewed by: Rosemarie Grantyn, Humboldt GABA that can be released and activate GABA receptors in neighboring neurons. These University Medical School (Charité), exciting new findings for glial GABA raise further interesting questions about the source Germany of GABA, its mechanism of release and regulation and the functional role of glial GABA. In Laszlo Heja, Hungarian Academy of this review, we highlight recent studies that identify the presence and release of GABA in Sciences, Hungary glial cells, we show several proposed potential pathways for accumulation and modulation *Correspondence: C. Justin Lee, Center for Neural of glial intracellular and extracellular GABA content, and finally we discuss functional roles Science and Center for Functional for glial GABA in the brain.
    [Show full text]
  • Glutamate Receptor Activation Triggers a Calcium- Dependent and SNARE Protein-Dependent Release of the Gliotransmitter D-Serine
    Glutamate receptor activation triggers a calcium- dependent and SNARE protein-dependent release of the gliotransmitter D-serine Jean-Pierre Mothet*†, Loredano Pollegioni‡, Gilles Ouanounou*, Magalie Martineau*, Philippe Fossier*, and Ge´ rard Baux* *Laboratoire de Neurobiologie Cellulaire et Mole´ culaire, Centre National de la Recherche Scientifique Unite´ Propre de Recherche 9040, Institut Fe´de´ ratif de Neurobiologie Alfred Fessard, F-91198 Gif-sur-Yvette, France; and ‡Department of Biotechnology and Molecular Sciences, University of Insubria, 21100 Varese, Italy Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved February 25, 2005 (received for review November 19, 2004) The gliotransmitter D-serine is released upon (S)-␣-amino-3-hydroxy- increase, because efflux of the transmitter is altered by manip- 5-methyl-4-isoxazolepropionic acid͞kainate and metabotropic glu- ulations of intracellular and extracellular calcium ion concen- tamate receptor stimulation, but the mechanisms involved are trations. Furthermore, treatment of primary astrocytes or glioma unknown. Here, by using a highly sensitive bioassay to continu- cells with tetanus neurotoxin (TeNT), which selectively cleaves ously monitor extracellular D-serine levels, we have investigated the vesicle-associated SNARE proteins VAMP2 and VAMP3 the pathways used in its release. We reveal that D-serine release is (8, 9), or with concanamycin A, a compound that inhibits the inhibited by removal of extracellular calcium and augmented by vacuolar-type Hϩ-ATPase (10), strongly reduced the release of ؉ increasing extracellular calcium or after treatment with the Ca2 D-serine. Finally, we demonstrate that a large part of D-serine is ionophore A23187. Furthermore, release of the amino acid is stored in VAMP2-bearing vesicles, as revealed by sucrose- considerably reduced after depletion of thapsigargin-sensitive gradient analysis and confocal microscopy.
    [Show full text]
  • Proceedings from the 2015 UK-Korea Neuroscience Symposium
    www.ukorea.ac.uk/pnf PROCEEDINGS OF THE UK-KOREA NEUROSCIENCE FORUM NEW CONCEPTS OF NEUROSCIENCE FOR BASIC RESEARCH AND THERAPEUTIC ADVANCES The 8th UK-KOREA Neuroscience Symposium The Latimer Room, Clare College, Cambridge, United Kingdom 15-16 Sept. 2015 The 8th UK-KOREA Neuroscience Symposium Professor Youngchan Lee Professor Doochul Kim President of Korea Health Industry President of Institute for Basic Science Development Institute (KHIDI), (IBS), Republic of Korea Republic of Korea Dear colleagues and friends, I would like to congratulate everyone involved in hosting I would like to extend a warm welcome to everyone “The 8th UK-Korea Neuroscience Symposium”, which attending the 8th UK-Korea Neuroscience Symposium. will bring together distinguished scientists from the UK Over the past ten years UK-Korea Neuroscience and Korea. I am confident that this symposium will foster Symposia have played a vital role in bridging the gap new research relationships, and encourage our nations between neuroscience and medical research in the UK to increasingly share knowledge, ideas, and resources. and Korea, as well as being committed to ensuring our In this regard, I am delighted that the Institute for Basic research helps to address global ageing issues with Science (IBS) is actively supporting this symposium excellence and impact. since hosting last year’s at IBS Center for Synaptic Brain This symposium will feature insightful speakers from a Dysfunctions. As the president of IBS, I offer my diverse cross section of neuroscience including wholehearted support to the symposium so that we can neurodegenerative disease research. Basic, medical, and share our research outcomes and make progress in translational advancements will be highlighted, from which neuroscience research.
    [Show full text]
  • Drosophila Glia: Models for Human Neurodevelopmental and Neurodegenerative Disorders
    International Journal of Molecular Sciences Review Drosophila Glia: Models for Human Neurodevelopmental and Neurodegenerative Disorders Taejoon Kim, Bokyeong Song and Im-Soon Lee * Department of Biological Sciences, Center for CHANS, Konkuk University, Seoul 05029, Korea; [email protected] (T.K.); [email protected] (B.S.) * Correspondence: [email protected] Received: 31 May 2020; Accepted: 7 July 2020; Published: 9 July 2020 Abstract: Glial cells are key players in the proper formation and maintenance of the nervous system, thus contributing to neuronal health and disease in humans. However, little is known about the molecular pathways that govern glia–neuron communications in the diseased brain. Drosophila provides a useful in vivo model to explore the conserved molecular details of glial cell biology and their contributions to brain function and disease susceptibility. Herein, we review recent studies that explore glial functions in normal neuronal development, along with Drosophila models that seek to identify the pathological implications of glial defects in the context of various central nervous system disorders. Keywords: glia; glial defects; Drosophila models; CNS disorders 1. Introduction Glial cells perform many important functions that are essential for the proper development and maintenance of the nervous system [1]. During development, glia maintain neuronal cell numbers and engulf unnecessary cells and projections, correctly shaping neural circuits. In comparison, glial cells in the adult brain provide metabolic sustenance and critical immune support. Thus, the dysfunction of glial activity contributes to various central nervous system (CNS) disorders in humans at different stages of life [2]. Accordingly, the need for research regarding the initiation as well as the progression of disorders associated with glial cell dysfunction is increasing.
    [Show full text]
  • Astrocyte Regulation of Synaptic Depression and Facilitation Maurizio De Pittà1, Vladislav Volman2,3, Hugues Berry4, and Eshel Ben-Jacob1,2,*
    A tale of two stories: astrocyte regulation of synaptic depression and facilitation Maurizio De Pittà1, Vladislav Volman2,3, Hugues Berry4, and Eshel Ben-Jacob1,2,* 1. School of Physics and Astronomy, Tel Aviv University, 69978 Ramat Aviv, Israel 2. Center for Theoretical Biological Physics, UCSD, La Jolla, CA 92093-0319, USA 3. Computational Neurobiology Laboratory, The Salk Institute, La Jolla, CA 92037, USA 4. Project-Team BEAGLE, INRIA Rhône-Alpes, Université de Lyon, LIRIS, UMR5205, F-69603, France *Corresponding author: Eshel Ben-Jacob: [email protected], Tel.: +972-3-640-7845 Fax: +972-3-642-5787 Citation: De Pittà M, Volman V, Berry H, Ben-Jacob E, 2011 A tale of two stories: astrocyte regulation of synaptic depression and facilitation. PLoS Comput. Biol. 7(12): e1002293. doi:10.1371/journal.pcbi.1002293 De Pittà et al., Astrocyte regulation of presynaptic plasticity PLoS Comput Biol 7(12): e1002293 Abstract Short-term presynaptic plasticity designates variations of the amplitude of synaptic information transfer whereby the amount of neurotransmitter released upon presynaptic stimulation changes over seconds as a function of the neuronal firing activity. While a consensus has emerged that the resulting decrease (depression) and/or increase (facilitation) of the synapse strength are crucial to neuronal computations, their modes of expression in vivo remain unclear. Recent experimental studies have reported that glial cells, particularly astrocytes in the hippocampus, are able to modulate short-term plasticity but the mechanism of such a modulation is poorly understood. Here, we investigate the characteristics of short-term plasticity modulation by astrocytes using a biophysically realistic computational model.
    [Show full text]
  • Astroglial Networks: a Step Further in Neuroglial and Gliovascular Interactions
    REVIEWS neuron–glia INTERACTIONS Astroglial networks: a step further in neuroglial and gliovascular interactions Christian Giaume*, Annette Koulakoff*, Lisa Roux*, David Holcman‡ and Nathalie Rouach* Abstract | Dynamic aspects of interactions between astrocytes, neurons and the vasculature have recently been in the neuroscience spotlight. It has emerged that not only neurons but also astrocytes are organized into networks. Whereas neuronal networks exchange information through electrical and chemical synapses, astrocytes are interconnected through gap junction channels that are regulated by extra- and intracellular signals and allow exchange of information. This intercellular communication between glia has implications for neuroglial and gliovascular interactions and hence has added another level of complexity to our understanding of brain function. Over the past three decades our understanding of inter- Connexins in astroglial networks cellular communication between glia has fundamentally Connexins and gap junctions. Gap junctions (BOX 1) changed from the notion that they are organized as a are expressed extensively in the nervous system. One syncytium — a multinucleate mass of cytoplasm result- of the first reports of direct cell-to-cell communication ing from the fusion of cells — to the recognition that presented electrophysiological evidence that gap junc- they are organized into networks. Indeed, in the 1970s tions allowed transmission between neurons at electri- the identification of a large number of gap junctions led cal synapses4. A few years later it was demonstrated that to the statement: “Adjacent glial cells, however, includ- non-neuronal cells were also extensively coupled by cell- ing those of mammals, are linked to each other by gap to-cell junctions5. In subsequent years, the ultrastructural junctions.
    [Show full text]
  • Astroglial Connexin43 Contributes to Neuronal Suffering in a Mouse Model of Alzheimer’S Disease
    Cell Death and Differentiation (2016) 23, 1691–1701 & 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 1350-9047/16 www.nature.com/cdd Astroglial connexin43 contributes to neuronal suffering in a mouse model of Alzheimer’s disease CYi1,2,3, X Mei1,2,3, P Ezan1,2,3, S Mato4,5, I Matias6,7, C Giaume1,2,3 and A Koulakoff*,1,2,3 In Alzheimer’s disease (AD), astrocyte properties are modified but their involvement in this pathology is only beginning to be appreciated. The expression of connexins, proteins forming gap junction channels and hemichannels, is increased in astrocytes contacting amyloid plaques in brains of AD patients and APP/PS1 mice. The consequences on their channel functions was investigated in a murine model of familial AD, the APPswe/PS1dE9 mice. Whereas gap junctional communication was not affected, we revealed that hemichannels were activated in astrocytes of acute hippocampal slices containing Aβ plaques. Such hemichannel activity was detected in all astrocytes, whatever their distance from amyloid plaques, but with an enhanced activity in the reactive astrocytes contacting amyloid plaques. Connexin43 was the main hemichannel contributor, however, a minor pannexin1 component was also identified in the subpopulation of reactive astrocytes in direct contact with plaques. Distinct regulatory pathways are involved in connexin and pannexin hemichannel activation. Inflammation triggered pannexin hemichannel activity, whereas connexin43 hemichannels were activated by the increase in resting calcium level of astrocytes. Importantly, hemichannel activation led to the release of ATP and glutamate that contributed to maintain a high calcium level in astrocytes placing them in the center of a vicious circle.
    [Show full text]
  • The Role of Amino Acids in Neurotransmission and Fluorescent Tools for Their Detection
    International Journal of Molecular Sciences Review The Role of Amino Acids in Neurotransmission and Fluorescent Tools for Their Detection Rochelin Dalangin 1, Anna Kim 1 and Robert E. Campbell 1,2,* 1 Department of Chemistry, University of Alberta, Edmonton, AB T6G 2G2, Canada; [email protected] (R.D.); [email protected] (A.K.) 2 Department of Chemistry, Graduate School of Science, The University of Tokyo, Bunkyo City, Tokyo 113-0033, Japan * Correspondence: [email protected]; Tel.: +1-7804921849 Received: 29 July 2020; Accepted: 24 August 2020; Published: 27 August 2020 Abstract: Neurotransmission between neurons, which can occur over the span of a few milliseconds, relies on the controlled release of small molecule neurotransmitters, many of which are amino acids. Fluorescence imaging provides the necessary speed to follow these events and has emerged as a powerful technique for investigating neurotransmission. In this review, we highlight some of the roles of the 20 canonical amino acids, GABA and β-alanine in neurotransmission. We also discuss available fluorescence-based probes for amino acids that have been shown to be compatible for live cell imaging, namely those based on synthetic dyes, nanostructures (quantum dots and nanotubes), and genetically encoded components. We aim to provide tool developers with information that may guide future engineering efforts and tool users with information regarding existing indicators to facilitate studies of amino acid dynamics. Keywords: amino acids; neurotransmission; fluorescence; imaging; biosensors; neurotransmitters; indicators 1. Introduction Neurons communicate to each other by the release of chemicals stored in synaptic vesicles across specialized gaps known as synapses. These chemicals diffuse across the synapse and bind to their target receptors on adjacent neurons to modulate their physiological states.
    [Show full text]
  • Modulation of Microglial Process Convergence Toward Neuronal Dendrites by Extracellular Calcium
    The Journal of Neuroscience, February 11, 2015 • 35(6):2417–2422 • 2417 Brief Communications Modulation of Microglial Process Convergence Toward Neuronal Dendrites by Extracellular Calcium X Ukpong B. Eyo,1 Nan Gu,1,2 Srijisnu De,1 Hailong Dong,2 Jason R. Richardson,3 and Long-Jun Wu1,4 1Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854, 2Department of Anesthesia, the Fourth Military Medical University Xijing Hospital, Xi’an, China, 710032, 3Department of Environmental and Occupational Medicine, Rutgers University Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, and 4Department of Physiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China, 230032 Extracellular calcium concentrations in the brain fluctuate during neuronal activities and may affect the behavior of brain cells. Microglia are highly dynamic immune cells of the brain. However, the effects of extracellular calcium concentrations on microglial dynamics have not been investigated. Here, we addressed this question in mouse brain slices and in vivo using two-photon microscopy. We serendipi- tously found that extracellular calcium reduction induced microglial processes to converge at distinct sites, a phenomenon we termed microglial process convergence (MPCs). Our studies revealed that MPCs target neuronal dendrites independent of neuronal action potentialfiringandismediatedbyATPreleaseandmicroglialP2Y12receptors.Theseresultsindicatethatmicrogliamonitorandinteract with neurons during conditions of cerebral calcium reduction in the normal and diseased brain. Key words: calcium reduction; microglia; microglial process convergence; neuronal dendrites; P2Y12 receptor Introduction tained at ϳ2mM (Clapham, 2007). This ϳ20,000-fold gradient 2ϩ Microglia are the principal resident immune cells of the CNS between compartments is established because Ca is a major actively involved in the developmental pruning of synapses mediator of cell signaling.
    [Show full text]